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15N CPMG Relaxation Dispersion for the Investigation of Protein Conformational Dynamics on the µs-ms Timescale
Published on: April 19, 2021
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Conformational Entropies and Order Parameters: Convergence, Reproducibility, and Transferability
Samuel Genheden1, Mikael Akke2, Ulf Ryde1
1Department of Theoretical Chemistry, Lund University , P.O. Box 124, SE-221 00 Lund, Sweden.
Journal of Chemical Theory and Computation
|November 19, 2015
Summary
Conformational entropy is key to protein function. Combining NMR spectroscopy with molecular dynamics (MD) simulations shows per-residue entropy is reproducible, but total entropy and dictionaries vary between proteins.
Area of Science:
- Biophysics
- Computational Biology
- Structural Biology
Background:
- Conformational entropy significantly impacts protein folding and biological functions like ligand binding.
- Nuclear Magnetic Resonance (NMR) spectroscopy offers atomic-resolution insights into conformational entropy.
- Molecular Dynamics (MD) simulations can complement NMR data, particularly through order-parameter-to-entropy dictionaries.
Purpose of the Study:
- To critically assess the reproducibility, convergence, and transferability of using MD simulations to estimate protein conformational entropy.
- To investigate the reliability of per-residue and total conformational entropy calculations.
- To evaluate the protein- and state-dependency of order-parameter-to-entropy dictionaries.
Main Methods:
- Analysis of long (380 ns - 1 ms) MD trajectories for five distinct proteins.
- Calculation and comparison of order parameters and conformational entropies over various time windows (10-100 ns).
- Assessment of reproducibility between independent MD trajectories and transferability of derived dictionaries.
Main Results:
- Per-residue conformational entropies and order parameters show good convergence and reproducibility across independent MD trajectories.
- Discrepancies in total conformational entropy can arise, especially during rare conformational state transitions.
- The order-parameter-to-entropy dictionary is highly protein- and sampling-dependent but less sensitive to the MD force field.
Conclusions:
- Per-residue entropy estimation using MD is generally reliable, but caution is needed for total entropy calculations involving rare events.
- Order-parameter-to-entropy dictionaries exhibit poor transferability between different proteins.
- Dictionaries show better transferability between different conformational states of the same protein, necessitating protein-specific derivations.
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